I’m so sorry

Barts-MS rose-tinted-odometer:  zero-★’s (Black Monday #000000)

I heard last week that one of my patients sadly succumbed to COVID-19. This is not the first person with MS to die of COVID-19 but is a reminder of how fickle life can be. I have contacted my patient’s partner to say how sorry I am. The question I am asking myself is; could this death have been prevented? Yes, almost certainly. However, I suppose this answer applies to all COVID-19 related deaths. 

Although the official global death toll from COVID-19 is 4.6m the unofficial estimate is 15.2m (95%CI 9.4m-18.2m), which means most of us will know someone who has died of COVID-19 (see The Economist; The pandemic’s true death toll, 5th Sept. 2021).

We should count ourselves lucky in the UK because we have a very high vaccination rate that has clearly reduced the number of people getting severe COVID-19 and dying from COVID-19. Sadly, however, being double-vaccinated is no guarantee of protection. Data from Public Health England (PHE) reveals that of all the people who died within 28 days of testing positive for the delta variant between 1 February and 19 July, 49% (224) had had two vaccine doses; almost all of these people, 220, were aged 50 or older (Public Health England. Investigation of SARS-CoV-2 variants of concern: technical briefings. 23 July). 

What does this mean for pwMS? This means we are not out of the woods yet. Please remain vigilant and careful. This particularly applies to those of you who have not been vaccinated and those on an anti-CD20 or S1P-modulator, in whom vaccine responses are likely to be blunted. People with MS are being classified by the government as being vulnerable and hence you will be offered a booster dose later this year. 

For those of you who have lost a loved one to COVID-19, there is a very good series of articles in this week’s BMJ on grief and grieving, which I recommend you read. Lucy Selman’s essay touched a raw nerve when I read it and many of the issues she discusses are particularly pertinent to how I am feeling this morning. It is hard, harder than you think, being a healthcare professional during the pandemic.

Lucy Selman. Covid grief has cracked us open: how clinicians respond could reshape attitudes to bereavement. BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1803 (Published 10 August 2021)

Excerpts

……. For people working in healthcare, grief brings home the ultimate futility of medicine as a lifesaving endeavour. Despite the best efforts of doctors, we all eventually die. Grief teaches us that medicine is about so much more than extending life.

…… Accommodating the ubiquity of sadness, loss, and grief makes some separation and compartmentalisation seem inevitable, even a useful coping strategy, for those who practise medicine. 

……. Clinicians are often encouraged or required, overtly or implicitly, to disregard and not talk about their own grief in the name of efficient patient care. Despite evidence of significant grief among clinicians, patient deaths are often not discussed.

…… But sequestering grief into the “private” realm outside of medical practice can have unintended negative consequences for clinicians and patients and their families, rendering us all more alone. Denying grief, hiding it away, hiving it off to a personal self, distinct from the professional, is to deny its place in life and to deny our humanity. In the context of a pandemic in which colleagues, patients, and loved ones have died, leaving no room at the table for grief renders life inauthentic.

…… Working with death and grief elides professional barriers. It urges us to bring our vulnerability with us, meeting the patient as a person but also, crucially, bringing our own person with us. That does not mean burdening patients with our own suffering or failing to maintain helpful boundaries. Rather, responding with compassion towards patients requires us to understand and respect our own need to process emotions.

……. Grief prompts us to consider how we treat ourselves as well as how we treat the person in front of us professionally. Being open about our own experiences of grief, and showing the strength of vulnerability, is a powerful statement to patients, carers, and colleagues that can help shift society’s attitude to grief. Individually, this can bring about a deepening and maturity of medical practice. Bringing the insights that grief affords into our professional and personal lives could have huge personal and societal benefits.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Mortality: what risk would you be prepared to take?

Barts-MS rose-tinted-odometer: ZERO-★’S (Black Tuesday – a tear for my beloved country #000000)

As you are aware by now I am a proponent of flipping the pyramid and using high-efficacy DMTs first-line including immune-reconstitution therapies (IRTs) such as alemtuzumab and AHSCT. I justify the latter two options based on the fact that given sufficient time the vast majority of pwMS will become disabled and  the real cost of MS to people with MS cannot be underestimated; loss of employment, poor relationships, cognitive impairment, fatigue, depression, anxiety, etc. I think you get the gist; MS is a bad disease. 

Alemtuzumab and HSCT are the two standout treatment options that offer pwMS the best chances of long-term remission and in some pwMS it may offer a cure. What impresses me about these two options is their impact on the end-organ, i.e. brain volume loss. After rebaselining at 12 months, pwMS treated with these two options lose brain volume on average at a rate that is within the normal range for age. The other DMTs don’t do this. The downside is that these two treatment options come with more risks. These two real-world studies below report 2 deaths out of 121 (2.5%) alemtuzumab-treated patients in Finland and 3 out of 120 HSCT-treated patients in London. Would you be willing to take these chances of dying to treat your MS with the potential for long term remission, possibly a cure and to protect your most precious end-organ the brain? 

Rauma et al. Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients. J Neurol. 2021 Jul 13. doi: 10.1007/s00415-021-10664-w.

Background: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.

Objectives: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.

Methods: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.

Results: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.

Conclusions: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Nicholas et al. Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series. Neurology. 2021 Jul 12;10.1212/WNL.0000000000012449. 

Objective: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.

Methods: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined.

Results: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure.

Conclusions: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.

Classification of evidence: this study is rated Class IV because of the uncontrolled, open-label design.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

Twitter   /  LinkedIn  /  Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#MSCOVID19 – a pyrrhic victory

Some of you may have read and being appalled by the following piece in this morning’s Guardian.

Robert Booth. Coronavirus: real care home death toll double official figure, study says. 13th May 2020

Excerpt: “More than 22,000 care home residents in England and Wales may have died as a direct or indirect result of Covid-19, academics have calculated – more than double the number stated as passing away from the disease in official figures.”

The hidden burden of COVID-19 goes way and beyond care homes. I was on a Zoom video conference with my UK colleagues last week and each person was asked about their centre’s COVID-19 experience. Almost everyone had had a COVID-19 related MS death. The tragedy was the deaths tended to be in older people with MS who were more disabled and with comorbidities. I am aware of two MS deaths in our patch, both bed-bound with end-stage MS. Whether or not these patients died from COVID-19 related problems is unknown. Both deaths have been ascribed to complications of MS. 

Forget about the deaths what about MS disease activity? Before COVID-19 it was very unusual to have patients on established DMTs have severe relapses. Severe attacks were typically seen in patients presenting with their first attack or in patients who were non-adherent to their DMTs. 

Since the lockdown, I have had three patients who have had severe relapses waiting to be initiated on treatment. One who has been furloughed and decided to be locked-down in her parents home far away from London. One waiting to start a DMT, but had delays in relation to baseline screening bloods and making a decision about treatment. As she has now had a severe and disabling brainstem or cerebellar relapse this shifts her into the high-disease activity group so she is now eligible for natalizumab. The latter could be viewed as some kind of “COVID-19 pyrrhic victory” as she now gets to be put on a high efficacy therapy. Fortunately, she is young so she should make a reasonable recovery from the relapse, but the damage has been done and some of her precious brain reserves has been shredded and lost forever. 

The final patient is a bit of a procrastinator and he decided to delay starting his treatment until after the peak of the COVID-19 epidemic. If there was no COVID-19 he would have almost certainly be treated two months ago, which would have potentially prevented the relapse. 

I would be interested to hear if any of you have had similar experiences, i.e. poor outcomes due to a delay in your treatment or untoward events due to your MS service being mothballed during the COVID-19 crisis.

I have little doubt that people with MS will be paying the price for COVID-19 for years to come. I suspect many will have been started on lower efficacy DMTs, some will have had their DMTs stopped or switched to lower efficacy or supposedly safer DMTs, others would have had their treatment initiation delayed and other would have had repeat dosing postponed to some yet to be determined date in the future. In addition, many people with very active MS who were lined-up to undergo HSCT have had their procedure delayed indefinitely. 

I wonder what the true cost of the above will be for people with MS?

CoI: multiple

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